Major depressive disorder (MDD) is a leading cause of disability in North America and in the world. For many patients with depression, full symptom remission remains elusive despite multiple trials of antidepressants. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, half of patients responded to an initial antidepressant trial, whereas a third of patients never achieved remission despite multiple adequate antidepressant trials.1 As every clinician knows, these outcomes are in-adequate.

For patients who do not respond to initial pharmacological treatment, several options exist. For the purposes of this article, we focus on psychopharmacological and related interventions. However, we recommend that all of these interventions occur in the context of a comprehensive treatment program that includes medications, psychotherapy, and other interventions.

Standard approaches to pharmacology include the optimization of the current treatment regimen and within-class or between-class switching. Before concluding that an antidepressant has failed, clinicians should ensure that adherence, dose, and duration are sufficient. An antidepressant trial should last at least 6 weeks and be at the minimum established clinically effective dose; some argue that a dose as high as two-thirds the maximum recommended dose is appropriate.

Antidepressant augmentation is another approach. Augmentation using an antidepressant with established efficacy may also be referred to as combination therapy. This may be more effective than other options, but it carries the risks of polypharmacy, such as drug-drug interactions and increased adverse-effect burden.

In this article, we briefly review the current options for pharmacological augmentation in MDD and their associated literature. Table 1 presents a summary of current augmentation strategies.

Traditional augmentation agents: STAR*D results

Lithium. Augmentation with lithium is one of the oldest strategies, and it is believed to work through the enhancement of serotonergic neurotransmission. Findings from 10 placebo-controlled trials of lithium augmentation (at dosages from 600 to 1200 mg/d, with serum levels of 0.5 to 1 mEq/L) indicate that lithium augmentation was more effective than placebo.2 One caveat with the lithium data is that the vast majority of these studies used a TCA as the principal antidepressant agent. Other limitations included variable lithium doses and outcome measures.

The evidence that exists for lithium augmentation of SSRIs is more sobering. Studies by Fava and colleagues3,4 showed no benefit of this augmentation compared with simply increasing the dose of the primary antidepressant. Additional factors to review when considering lithium augmentation are adverse effects, potential toxicity, and need for serum monitoring. Notably, in STAR*D, when lithium augmentation was compared with thyroid hormone augmentation, the two approaches were equally efficacious, but lithium had a higher adverse-effect burden.5

Thyroid hormone. Thyroid hormone augmentation, typically with triidothyronine (T3) but sometimes with thyroxine, is hypothesized to work by enhancing noradrenergic neurotransmission or correcting a brain bioenergetic deficiency. At a target dosage of 50 μg/d, treatment tends to be well tolerated with few adverse effects. As with lithium, much of the data on T3 augmentation involves TCAs rather than SSRIs.

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SECTION EDITORS: DEPRESSION

Marlene P. Freeman, MD is Associate Professor of Psychiatry at Harvard Medical School, Medical Director OF CTNI Director of Clinical Services, Perinatal and Reproductive Psychiatry Program at Massachusetts General Hospital in Boston.

George I. Papakostas, MD is Director of Treatment-Resistant Depression Studies in the Department of Psychiatry at Massachusetts General Hospital and Associate Professor of Psychiatry at Harvard Medical School in Boston.